Process for a phenylthiobutyl-isoquinoline and intermediates therefor

ABSTRACT

Intermediate compounds useful for making phenylthiobutyl-isoquinoline compounds of formula

This is a divisional of application(s) Ser. No. 09/044,439 filed on Mar.19, 1998 now U.S. Pat. No. 6,130,348.

BACKGROUND OF THE INVENTION

The compound phenylthiobutyl-isoquinoline of the formula

and its preparation starting from L-serine is described, e.g., in U.S.Pat. No. 5,484,926, incorporated herein by reference. This compound is avaluable intermediate for the manufacture of pharmacologically activecompounds, suitable for the treatment of viral infections, especiallythose caused by HIV and other retroviruses, described in U.S. Pat. No.5,484,926, e.g., at columns 16 and 17, such as represented by formula

wherein Ph is phenyl

and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

The present invention relates to a new method for making compounds offormula

and intermediates for making compounds of formula II.

The compounds of this invention are useful intermediates for themanufacture of pharmacologically active compounds suitable for thetreatment of viral infections, particularly, those caused by HIV andother retroviruses.

The method of the present invention is characterized by less reactionsteps, more convenient reaction conditions and a higher overall yield ofthe desired stereoisomer of formula II. Particularly, in accordance withthe method of the present invention, protection of a carbamate group ofan intermediate phenylthio compound by a silyl group leads to aconsiderable increase in yield compared to that of prior methods formaking compounds of formula II.

DETAILED DESCRIPTION OF THE INVENTION

The method of the present invention comprises

(a) reacting diprotected L-serine of formula

wherein R is lower alkyl and R¹ is lower alkyl or benzyl, with mesyl ortosyl chloride and a thiophenolate;

(b) reacting the resulting phenylthio compound of formula

with halogenated methyllithium;

(c) reducing a resulting halogen ketone of formula

wherein X is halogen,

to the corresponding halogen alcohol of formula

(d) treating the halogen alcohol of formula V with abase to form the[(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]carbamic acid ester offormula

(e) reacting the carbamic acid ester of formula IV withN-tert.-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxarnide offormula

and

(f) treating the resulting compound of formula

with a base to yield the compound of formula II above.

The term “lower-alkyl” used throughout the specification and claimsrefers to straight- or branched-chain saturated hydrocarbon residueswith 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, tert.-butyl, a pentyl or a hexyl groupwith methyl and ethyl being preferred, especially for R¹. Especiallypreferred in connection with the present invention are compounds whereinR¹ is methyl. Halogen denotes chlorine, bromine and iodine with chlorinebeing preferred.

The starting diprotected L-serines of formula VIII are known compoundsand can easily be prepared from L-serine via reacting the correspondingL-serine lower alkyl esters with the corresponding chloroformates.

The phenylthio compounds of formula VII may be prepared using methodsknown in the art (e.g. Sasaki et al., Tetrahedron Letters 28, 6069(1987)). The amino- and carboxy-protected L-serine is transformed intoits tosylate or mesylate in the presence of an amine such as pyridine ortriethylamine in an aprotic solvent such as methylene chloride or aceticacid ester and then reacted with a thiophenolate. The thiophenolate canbe prepared in situ from thiophenol and a strong base, at lowtemperature, preferably a temperature from −10° C. up to 0° C.

Any conventional halomethylating agent can be used to halomethylate thephenylthio compounds of formula VII to form the halogen ketone compoundsof formula VI. The halomethylation of the resulting phenylthio compoundVII is preferably effected using halogenated methylithium which isgenerated in situ. The latter is conveniently formed using dihalogenatedmethane, e.g., dichloro-, dibromo- or diiodomethane, preferably usingbromochloromethane, and a lower-alkyl-lithium, such as, for example,butyllithium or hexylithium, in an ether, preferably tetrahydrofuran, at−20° to −120° C., preferably −80° C.

In accordance with the method of the present invention, thehalomethylation of the phenylthio compound VII to the halogen ketone VIis carried out by

(a) silylating a carbamate group of a compound of formula VII in thepresence of a lower-alkyl-lithium to form a silyl-protected compound;and

(b) alkylating the silyl-protected compound in the presence ofdihalogenated methane with a lower-alkyl-lithium to produce a halogenketone of formula VI.

Preferred silyl-protected compounds of the present invention includecompounds of the general formula VII-A and/or VII-B formed as anintermediate

In accordance with the present invention, any conventional method forproducing the silyl-protected compounds of formulas VII-A and VII-B canbe used. Suitable silylating agents for use with the present inventioninclude organochlorosilanes of the formula ClSi(R², R³, R⁴), wherein R²,R³ and R⁴ are lower-alkyl or phenyl. A preferred organochlorosilane ischlorotrimethylsilane.

The method of the present invention for making the halogen ketone offormula VI provides new and unexpected results. Surprisingly, theprotection of the carbamate group present in compound VII by a silylgroup yielding compounds VII-A and/or VII-B as intermediates leads to aconsiderable increase in yield of the halogen ketone compounds offormula VI. Furthermore, this novel method for producing the halogenketone compounds of formula VI can be used in a process for making thecompounds of formula II to provide increased yields of the compounds offormula II compared to prior methods.

In accordance with the present invention, any conventional means can beused to alkylate the silyl-protected compounds of formula VII-A andVII-B. Preferred alkylating agents are lower-alkyl-lithium compoundssuch as butyllithium or hexyllithium. Moreover, an almost completehalomethylation of the phenylthio compounds of formula VII can beachieved using significantly less lower-alkyl-lithium and dihalogenatedmethane compared to amounts typically used in conventionalhalomethylation methods. In accordance with the present invention, thehalogen ketone VI can be reduced to the corresponding alcohol of formulaV with a hydride in a solvent such as toluene, tetrahydrofuran or analcohol, preferably methanol, ethanol or isopropanol, at a temperaturebetween −30 and 80° C., preferably between −15° C. and 50° C.,optionally under reduced pressure, using sodiumbis-(2-methoxy-ethoxy)-aluminium hydride, lithium aluminium hydride,lithium aluminium tri-tert.-butoxyhydride, sodium borohydride,tetramethylammonium borohydride or, preferably, using an aluminiumtri-alkoxide or lithium aluminium tri-alkoxyhydride. The term “alkoxide”means lower alkoxy with the lower-alkyl residue being as defined above,such as, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, orisobutoxy, tert.-butoxy, as well as pentyloxy or hexyloxy groups. Thealuminium compounds can have identical or different alkoxy groups.Aluminium tri-isopropoxide and aluminium tri-sec.-butoxide areespecially preferred compounds. The reagents lithium aluminiumtri-tert.-butoxyhydride, aluminium tri-isopropoxide and aluminiumtri-sec.-butoxide gave unexpected high stereoselectivity in a molarratio of at least 9:1 of the (1S,2S) and (1S, 2R) isomeric halohydrinsV, which could be crystallized in >99% optical purity and with highyield.

The ring closure of the halohydrin of formula V to form thecorresponding epoxide of formula IV can be carried out by conventionalmeans, such as in a solvent, for example, ethanol or preferably, atoluene/water mixture in the presence of a base such as an alkaline oralkaline earth metal hydroxide, preferably sodium or potassiumhydroxide, at a temperature between 0° and 80° C., preferably 40-50° C.The epoxide which is formed need not be purified.

The reaction of the epoxide of formula IV with the isoquinoline X toform compound III can be carried out by any conventional means, such as,in a solvent, for example, a hydrocarbon, such as toluene, or alower-alkanol, preferably ethanol, while heating under reflux, atpreferably 20-100° C., and most preferably 80° C.

The cleavage of the N-protecting group from the compound of formula IIIcan be carried out by any conventional means such as, in a solvent, forexample, water, ethanol or a mixture thereof, using a base such assodium or potassium hydroxide while heating to the reflux temperature,preferably 20-100° C., especially 80° C.

A further aspect of the present invention is the new intermediatecompounds of formulas VII, VI, V, IV and VIII wherein R¹ is lower alkyl,namely, compounds of formulas VII-1. VI-1, V-1, IV-1 and III-1, as wellas the use of these new intermediate compounds for the preparation ofthe compound of formula II or pharmacologically active compoundssuitable for treating viral infections, such as the compound of formulaI and their salts mentioned above. A preferred embodiment of the newcompounds of this invention are those wherein R¹ is C₁₋₃ alkyl,especially methyl or ethyl.

Especially preferred compounds of formulas III, IV, V, VI and VII arethose wherein R and R¹ are methyl and X is chlorine, such as

methyl (1R, 2R)-[1-phenylthiomethyl-3-[(3S, 4aS,8aS)-3-tert.-butoxycarbamoyl-decahydroisoquinol-2-yl]-2-hydroxypropyl]-carbamate;

methyl [(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamate;

methyl (1R,2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbarnate;

methyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and

methyl (3-phenylthio-(R)-2-methoxycarbonylamino)-propionate.

Finally, the compounds of formulas II, III, IV, V, VI and VII, whenobtained by the method described hereinbefore or in the followingExamples, are a further aspect of the present invention.

A compound of formula I can be obtained, e.g., in accordance with themethod described in Example 23 of U.S. Pat. No. 5,484,926, using 70 mgof the compound of formula II, 24.6 mg of 3-hydroxy-2-methylbenzoicacid, 33 mg of DDC and 22mg of HOBTH₂O in 4 ml of THF.

The formation of pharmaceutically acceptable salts can be performed byconventional methods known in the art. The methanesulfonic acid salt,e.g., can be prepared as described in Example 75 of U.S. Pat. No.5,484,926 by dissolving 3.34 g of compound I in 30 ml of MeOH and 30 mlof methylene chloride and adding a solution of 596 mg of methanesulfonicacid in 10 ml of methylene chloride dropwise and working up of thereaction mixture to obtain the desired compound in pure form.

Reaction Scheme I summarizes the preferred reaction steps for thepreparation of compounds VIII to I wherein R and R¹ are methyl and X ischlorine, This reaction scheme is described in more detail in theexamples of the specification.

The following Examples illustrate the present invention in more detailwithout limiting it.

EXAMPLE 1

To a solution of 72.03 g L-serine-methylester hydrochloride in 400 ml ofwater were added at 0° C. 49.5 g of methyl chioroformate. The pH waskept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After2½ h at 0° C. the mixture was extracted with 6 portions of ethylacetate, the combined extracts were dried and evaporated to give 75.39 g(92%) of pure methyl 3-hydroxy-(S)-2-methoxycarbonylamino-propionate. IR(neat): 3380 m (NH, OH), 1720s, br. (C═O), 1535s (amide II). MS (EI):178/20 (M+H⁺).

EXAMPLE 2

To a solution of 8.86 g of methyl3-hydroxy-(S)-2-methoxycarbonylamino-propionate and 5.73 g ofmethanesulfonyl chloride in 80 ml of ethyl acetate were added at −10° C.5.06 g of triethylamine. After 1 hour at −10° C. the mixture was washedwith diluted aqueous hydrochloric acid (1N) and water, the ethyl acetatewas evaporated and the residue was dissolved in 15 ml ofdimethylformamide. The solution was treated at −20° C. with a solutionof 7.41 g of sodium thiophenolate in 30 ml of dimethylformamide andstirring was continued at −20° C. for 5 hours. The mixture was dilutedwith water and extracted with toluene and the toluene was evaporated togive 13.22 g (98%) of pure methyl(3-phenylthio-(R)-2-methoxycarbonylamino)-propionate. IR (neat): 3350w(NH), 1745s and 1702s (C═O), 1513s (amide II). MS (EI): 269/20(M⁺).

EXAMPLE 3

To a solution of 8.08 g of methyl(3-phenylthio-(R)-2-methoxycarbonylamino)- propionate in 75ml oftetrahydrofuran were added at −80° C., 18 ml of a 1.67M solution ofbutyllithium in hexane followed by addition of 3.58 g ofchlorotrimethylsilane. The suspension was treated with 4.66 g ofbromochloromethane followed by addition of 27 ml of a 1.67M solution ofbutyllithium in hexane at −80° C. The solution was quenched with 50 mlof 6% aqueous hydrochloric acid and warmed to 22° C. The layers wereseparated, the organic layer was washed with brine, dried and evaporatedto give 8.70 g approx. 70% pure methyl[3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate. A sample wascrystallized from tetrahydrofuran/hexane, m.p. 91-92.5° C. IR (KBr):3321s (NH), 1740s and 1681s (C═O), 1539s (anide II). MS (EI): 287/15(M⁺).

EXAMPLE 4

To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanolwere added 2.88 g of methyl[3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and thesuspension was stirred at 70° C./400 mbar for 4 hours. The mixture wascooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acidand the isopropanol was evaporated. The suspension was filtered and theresidue was recrystallized from toluene to give 2.18 g (75%)isomerically pure methyl (1R,²S)-[³-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate, m.p.113-114° C. IR (KBr): 3389m and 3327m (NH,.OH), 1695s (C═O), 1537s(amide II). MS (EI) : 289/35 (M⁺).

EXAMPLE 5

A mixture of 2.90 g of methyl (1R,²S)-[3chloro-2-hydroxy-l-(phenylthiomethyl)-propyl]-carbamate, 0.8 gsodium hydroxide, 20 ml toluene and 10 ml of water was stirred at 40° C.for 2 hours. The organic layer was washed with water and the solventevaporated. The residue containing methyl[(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamate was mixed with 12ml of ethanol and 2.38 g ofdecahydro-(4aS,.8aS)-isoquinoline-3(S)-N-tert.-butylcarboxamide andheated at reflux temperature for 5-10 hours. The solvent was evaporatedand the residue partitioned between water and dichloromethane. Theorganic layer was evaporated to give 4.4 g (90%) of methyl (1R,2R)-[1-phenylthiomethyl-3-[(3S, 4aS,8aS)-3-tert.-butoxycarbamoyl-decahydro-isoquinol-2-yl]-2-hydroxypropyl]-carbamate.IR (KBr): 3410m and 3320m (NH, OH), 1715s and 1660s (C═O), 1550s (amideII).

EXAMPLE 6

A suspension of 4.92 g of methyl (1R, 2R)-[1-phenyl-thiomethyl-3-[(3S,4aS,8aS)-3-tert.-butoxycarbaroyl-decahydroisoquinol-2-yl]-2-hydroxy-propyl]-carbamateand 2.69 g of sodium hydroxide in 10 ml of ethanol and 10 ml of waterwas heated at reflux for 3-5 hours. The solvent was evaporated and theresidue was partitioned between water and dichloromethane. The organiclayer was washed with water, dried and evaporated to give 3.9 g (90%)2-[3(R)-amino-2(R)-hydroxy4-phenylthio-butyl]-decahydro-(4aS,8aS)-isoquinoline-3(S)-N-tert.-butylcarboxamide.

EXAMPLE 7

To a solution of 240 g1 L-serine-methylester hydrochloride in 130 ml ofwater were added at 0° C. 29.8 g of benzyl chloroformate. The pH waskept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After3 h at 0° C. the mixture was extracted with 5 portions of ethyl acetate,the combined extracts were dried and evaporated to give 37.12 g (95%) ofpure methyl 3-hydroxy-(S)-2-benzyloxycarbonylamino-propionate. IR(neat): 3380m (NH, OH), 1720s, br. (C═O), 1540s (amide II).

EXAMPLE 8

To a solution of 8.86 g of methyl3-hydroxy-(S)-2-benzyloxycarbonylamino-propionate and 4.00 g ofmethanesulfonyl chloride in 60 ml of ethyl acetate were added at −10° C.3.54 g of triethylamine. After 1 hour at −10° C. the mixture was washedwith diluted aqueous hydrochloric acid (1N) and water, the ethylacetatewas evaporated and the residue was triturated with hexane. The crudemesylate was dissolved in 11 ml of dimethylformamide and treated at −20°C. with a solution of 5.19 g sodium thiophenolate in 22 ml ofdimethylformamide. After 5 hours at −20° C. the mixture was diluted withwater and extracted with toluene. The toluene was evaporated and theresidue was crystallized from toluene/hexane (1:9, v/v) to give 9.5 g(79%) of pure methyl(3-phenylthio-(R)-2-benzyloxycarbonylamino)-propionate. IR (KBr): 3339m(NH), 1742s and 1681s (C═O), 1533s (amide II).

EXAMPLE 9

To a solution of 10.36 g of methyl(3-phenylthio-(R)-2-benzyloxycarbonylamino)-propionate in 80 ml oftetrahydrofuran were added at −80° C. 18 ml of a 1.67M solution ofbutyllithium in hexane followed by addition of 3.58 g ofchlorotrimethylsilane. The suspension was treated with 4.66 g ofbromochloromethane followed by addition of 27 ml of a 1.67M solution ofbutyllithium in hexane at −80° C. The solution was quenched with 55 mlof 6% aqueous hydrochloric acid and warmed to 22° C. The layers wereseparated, the organic layer was washed with brine, dried and evaporatedto give 10.5 g approx. 75% pure benzyl[-3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate. IR (KBr):3350s (NH), 1730s and 1685s (C═O), 1520s (amide II).

EXAMPLE 10

To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanolwere added 3.64 g of benzyl[3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and themixture was stirred at 50° C./400 mbar for 4 hours. The mixture wascooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acidand the isopropanol was evaporated. The residue was partitioned betweenwater and dichioromethane and the organic layer was evaporated. Theresidue was chromatographed on silica to give 2.9 g (80%) of pure benzyl(1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate. IR(KBr): 3360br (NH, OH), 1690s (C═O), 1540s (amide II).

What is claimed is:
 1. A compound of formula

wherein R is lower alkyl and R¹ is methyl or ethyl.
 2. The compound ofclaim 1 wherein said compound is methyl(3-phenylthio-(R)-2-methoxycarbonylamino)-propionate.
 3. A compound offormula

wherein R¹ is lower alkyl and X is halogen.
 4. The compound of claim 3wherein R¹ is methyl or ethyl.
 5. The compound of claim 3 wherein saidcompound is methyl[3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate.
 6. Acompound of formula

wherein R¹ is lower alkyl and X is halogen.
 7. The compound of claim 6wherein R¹ is methyl or ethyl.
 8. The compound of claim 6 wherein saidcompound is methyl (1R, 2S)-[3-chloro-2-hydroxy- 1-(phenylthiomethyl)-propyl]-carbamate.
 9. A compound of formula

wherein R¹ is lower alky.
 10. The compound of claim 9 wherein R¹ ismethyl or ethyl.
 11. The compound of claim 9 wherein said compound ismethyl [(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamate.